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Endpoint:
basic toxicokinetics in vivo
Type of information:
other: compilation of data from the literature
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Objective of study:
absorption
excretion
metabolism
Qualifier:
no guideline required
Principles of method if other than guideline:
Survey and evaluation of the available literature.
The Committee evaluated 43 flavouring agents that are derivatives of phenethyl alcohol and phenoxyethyl alcohol . ... The group also includes four phenoxyethyl alcohol derivatives: phenoxyacetic acid (No. 1026), the sodium salt of a structurally related phenoxyacetic acid (No. 1029), a phenoxyethyl ester (No. 1027) and a phenoxyacetic acid ester (No. 1028). The evaluations were conducted with the Procedure for the Safety Evaluation of Flavouring Agents. None of these agents has previously been evaluated by the Committee.
GLP compliance:
not specified
Details on absorption:
Sodium phenoxyacetate (NaPhA) is easily soluble in water and it dissociates there to the toxicologically relevant anion phenoxyacetate (PhA-) and the physiologically occurring sodium ion.
From the Section on Absorption, distribution and excretion:
"When ingested in traditional foods, in foods to which they have been intentionally added or as hydrolysis products resulting from either condition, phenethyl and phenoxyethyl alcohols, phenylacetaldehyde and phenylacetic and phenoxyacetic acids are rapidly absorbed from the gastrointestinal tract. Once absorbed, the alcohols and aldehydes are rapidly oxidized to yield phenylacetic or phenoxyacetic acid derivatives, which are subsequently excreted in the urine, either free as in the case of phenoxyacetic acid or conjugated as in the case of phenylacetic acid (Williams, 1959; James et al., 1972; Sangster & Lindley, 1986; Hawkins & Mayo, 1986; Caldwell, 1987)."
"Phenoxyacetic acid was fed to male rabbits at a dose of 100–200 mg/kg bw, and some animals also received glycine in amounts corresponding to three equivalents of the acid. In this test, 44–72% of the phenoxyacetic acid was recovered unchanged in the urine within 6 h and 82–105% within 24 h. There was no evidence of conjugation with either glucuronic acid or glycine, even when the diet was supplemented with glycine. A rabbit that received an oral dose of 500 mg of the glycine conjugate of phenoxyacetic acid excreted 30% of the dose unconjugated in the urine after 18 h (Levey & Lewis, 1947).
In another study, 55% of an oral dose of an unspecified amount of phenoxyacetic acid was recovered in the urine of dogs and 61% in the urine of humans. No evidence for glycine or glucuronic acid conjugation was found (Thierfelder & Schempp, 1917)."
Conclusion:
Phenoxyacetic acid and sodium phenoxyacetate are easily and practically completely absorbed after oral administration. The common anion phenoxyacetate is excreted practically completely and unchanged in urine.
Details on excretion:
From the Section on Absorption, distribution and excretion:
"When ingested in traditional foods, in foods to which they have been intentionally added or as hydrolysis products resulting from either condition, phenethyl and phenoxyethyl alcohols, phenylacetaldehyde and phenylacetic and phenoxyacetic acids are rapidly absorbed from the gastrointestinal tract. Once absorbed, the alcohols and aldehydes are rapidly oxidized to yield phenylacetic or phenoxyacetic acid derivatives, which are subsequently excreted in the urine, either free as in the case of phenoxyacetic acid or conjugated as in the case of phenylacetic acid (Williams, 1959; James et al., 1972; Sangster & Lindley, 1986; Hawkins & Mayo, 1986; Caldwell, 1987)."
"Phenoxyacetic acid was fed to male rabbits at a dose of 100–200 mg/kg bw, and some animals also received glycine in amounts corresponding to three equivalents of the acid. In this test, 44–72% of the phenoxyacetic acid was recovered unchanged in the urine within 6 h and 82–105% within 24 h. There was no evidence of conjugation with either glucuronic acid or glycine, even when the diet was supplemented with glycine. A rabbit that received an oral dose of 500 mg of the glycine conjugate of phenoxyacetic acid excreted 30% of the dose unconjugated in the urine after 18 h (Levey & Lewis, 1947). "
"In another study, 55% of an oral dose of an unspecified amount of phenoxyacetic acid was recovered in the urine of dogs and 61% in the urine of humans. No evidence for glycine or glucuronic acid conjugation was found (Thierfelder & Schempp, 1917)."

Conclusion: PhAA is easily and practically completely absorbed after oral administration and is excreted practically completely and unchanged in urine (of rabbits).
Metabolites identified:
no
Details on metabolites:
From the Section on Absorption, distribution and excretion:
"When ingested in traditional foods, in foods to which they have been intentionally added or as hydrolysis products resulting from either condition, phenethyl and phenoxyethyl alcohols, phenylacetaldehyde and phenylacetic and phenoxyacetic acids are rapidly absorbed from the gastrointestinal tract. Once absorbed, the alcohols and aldehydes are rapidly oxidized to yield phenylacetic or phenoxyacetic acid derivatives, which are subsequently excreted in the urine, either free as in the case of phenoxyacetic acid or conjugated as in the case of phenylacetic acid (Williams, 1959; James et al., 1972; Sangster & Lindley, 1986; Hawkins & Mayo, 1986; Caldwell, 1987)."
"Phenoxyacetic acid was fed to male rabbits at a dose of 100–200 mg/kg bw, and some animals also received glycine in amounts corresponding to three equivalents of the acid. In this test, 44–72% of the phenoxyacetic acid was recovered unchanged in the urine within 6 h and 82–105% within 24 h. There was no evidence of conjugation with either glucuronic acid or glycine, even when the diet was supplemented with glycine. A rabbit that received an oral dose of 500 mg of the glycine conjugate of phenoxyacetic acid excreted 30% of the dose unconjugated in the urine after 18 h (Levey & Lewis, 1947). "
"In another study, 55% of an oral dose of an unspecified amount of phenoxyacetic acid was recovered in the urine of dogs and 61% in the urine of humans. No evidence for glycine or glucuronic acid conjugation was found (Thierfelder & Schempp, 1917)."

Conclusion: PhAA is easily and practically completely absorbed after oral administration and is excreted practically completely and unchanged in urine (of rabbits).

Cited reports and publications:

- Caldwell, J. (1987) Human disposition of [14C]-ORP/178. Unpublished report. Private communication. Submitted to WHO by Flavor and Extract Manufacturers’ Association of the United States.Cited by WHO 2003.

- Hawkins, D.R. & Mayo, B.C. (1986) Plasma kinetics of [14C]-ORP/178 in the rat. Unpublished report. Private communication. Submitted to WHO by Flavor and Extract Manufacturers’ Association of the United States.Cited by WHO 2003.

- Howes, D. Absorption and metabolism of 2-phenoxyethanol in rat and man. Cosmet.Toiletries, 103, 75, 1988. Cited by WHO 2003.

- James, M.O., Smith, R.L., Williams, R.T. & Reidenberg, M. (1972) The conjugation of phenylacetic acid in man, sub-human primates and some non-primate species. Proc. R. Soc. London B, 182, 25–35.Cited by WHO 2003.

- Levey, S. & Lewis, H.B. The metabolism of phenoxyacetic acid, its homologues, and some monochlorophenoxyacetic acids. New examples of oxidation. J. Biol. Chem., 168, 213–221,1947. Cited by WHO 2003.

- Sangster, S.A. & Lindley, M.G. (1986) Metabolism and excretion of ORP/178 in man. Unpublished report. Private communication. Submitted to WHO by Flavor and Extract Manufacturers’ Association of the United States.Cited by WHO 2003.

- Thierfelder, H. & Schempp, E. Behaviour of benzoylpropionic acid, phenethyl alcohol and phenoxyacetic acid in the body of men and dogs. Arch. Ges. Physiol., 167, 280–288, 1917. Cited by WHO 2003.

- Williams, R.T. Book: Detoxication Mechanisms - The Metabolism and Detoxication of Drugs, Toxic Substances and Other Organic Compounds, 2nd Ed., London, Chapman & Hall. 1959. Cited by WHO 2003.

Executive summary:

From WHO 2003, Section on Absorption, distribution and excretion:

"When ingested in traditional foods, in foods to which they have been intentionally added or as hydrolysis products resulting from either condition, phenethyl and phenoxyethyl alcohols, phenylacetaldehyde and phenylacetic and phenoxyacetic acids are rapidly absorbed from the gastrointestinal tract. Once absorbed, the alcohols and aldehydes are rapidly oxidized to yield phenylacetic or phenoxyacetic acid derivatives, which are subsequently excreted in the urine, either free as in the case of phenoxyacetic acid or conjugated as in the case of phenylacetic acid (Williams, 1959; James et al., 1972; Sangster & Lindley, 1986; Hawkins & Mayo, 1986; Caldwell, 1987)."

"Phenoxyacetic acid was fed to male rabbits at a dose of 100–200 mg/kg bw, and some animals also received glycine in amounts corresponding to three equivalents of the acid. In this test, 44–72% of the phenoxyacetic acid was recovered unchanged in the urine within 6 h and 82–105% within 24 h. There was no evidence of conjugation with either glucuronic acid or glycine, even when the diet was supplemented with glycine. A rabbit that received an oral dose of 500 mg of the glycine conjugate of phenoxyacetic acid excreted 30% of the dose unconjugated in the urine after 18 h (Levey & Lewis, 1947). "

"In another study, 55% of an oral dose of an unspecified amount of phenoxyacetic acid was recovered in the urine of dogs and 61% in the urine of humans. No evidence for glycine or glucuronic acid conjugation was found (Thierfelder & Schempp, 1917)."

Conclusion: Phenoxy acetic acid and sodium phenoxyacetate are easily and practically completely absorbed after oral administration. The common anion phenoxyacetate is excreted practically completely and unchanged in urine (of rabbits).

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
<2015
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Objective of study:
absorption
distribution
excretion
metabolism
Qualifier:
according to
Guideline:
other: OECD 427
Version / remarks:
2004; for the topical application.
Deviations:
not specified
Principles of method if other than guideline:
An analytical method is described to simultaneously determine phenoxyethanol and phenoxyacetic acid in biological matrices. Application to i.v. and dermal ADME in vivo studies. Only the in vivo studies are reported here.
GLP compliance:
not specified
Specific details on test material used for the study:
2-Phenoxyethanol (PE) and phenoxyacetic acid (PAA) were purchased from Tokyo Chemical Ind. (Tokyo, Japan).
Radiolabelling:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
Male Sprague–Dawley rats (8 weeks, body weight 230–280 g) were kept in plastic cages with free access to water and standard rat diet. Rats were housed at a temperature of 23 ± 2 °C with a 12-h light–dark cycle and relative humidity of 50 ± 10%, and were acclimatized for at least 1 week prior to the experiment.
Route of administration:
other: An i.v. injection study and a topical application study were performed.
Vehicle:
other: Isotonic saline for the i.v. study; two sunscreen formulations for the topical application.
Details on exposure:
Intravenous injection study:
After overnight fasting, PE was injected at doses of 0.2, 0.5, and 2 mg/kg (n = 8 per dose) via the penile vein. The dosing solutions were prepared by dissolving PE in isotonic saline at concentrations of 0.2, 0.5, and 2 mg/mL. The volume of injected dosing vehicles was kept constant (1 mL/kg) regardless of the dose level.

Topical application study
Two reference sunscreen formulations of emulsion and lotion were prepared to examine the percutaneous absorption of PE by modifying the formulations reported by the European Commission on Cosmetics and Medical Devices (2006). Each formulation consisted of 2 phases and the final product weighed 10 g. The final preparations were kept in light-resistant containers at room temperature until use.
Approximately 24 h prior to experimentation, rats were anesthetized by diethyl ether and the dorsal skin covering the area of 5 x 5 cm2 was shaved with an electric clipper. The shaved skin surface was gently wiped with acetone to remove sebum. After overnight fasting, each formulation was applied to the shaved dorsal skin of rats covering the area of 4 x 4 cm2 (n = 6 per each formulation). The applied amount of each formulation was 234 mg/kg, and the applied PE dose was 2.34 mg/kg.
At 12 h after topical application, the applied area was softly rinsed off with acetone to remove sunscreen remaining on the skin.
Duration and frequency of treatment / exposure:
Once.
Dose / conc.:
0.2 mg/kg bw/day (nominal)
Remarks:
For i.v. application.
Dose / conc.:
0.5 mg/kg bw/day (nominal)
Remarks:
For i.v. application.
Dose / conc.:
2 mg/kg bw/day (nominal)
Remarks:
For i.v. application.
Dose / conc.:
2.34 mg/kg bw/day (nominal)
Remarks:
PE within each of the 2 sunscreen formulations.
No. of animals per sex per dose:
I.v. experiment: 8 per dose.
Dermal experiment: 6 per formulation.
Control animals:
not specified
Details on study design:
Tissue distribution study:
The tissue distribution study was conducted in rats (n = 5) after constant rate intravenous infusion to steady-state. Prior to the infusion, a polyethylene tubing (0.58 mm i.d., 0.96 mm o.d., Natume, Tokyo, Japan) was implanted in jugular (for sampling) and femoral (for infusion) veins after anesthesia with intraperitoneal injection of Zoletil (20 mg/kg). Rats were allowed to recover for 2 days and fasted overnight. The rats were given continuous intravenous infusions for 2 h at a rate of 0.83 mg/kg/h. The infusion rate was determined as the product of the target steady state plasma concentration (Css = 100 ng/mL) and the systemic clearance obtained from the intravenous injection study. The dosing solution was prepared by dissolving PE in isotonic saline at a concentration of 0.195 mg/mL. Blood samples were collected at 0, 15, 30, 45 min, and 1, 1.25, 1.5, 1.75, and 2 h after initiation of the intravenous infusion. Plasma samples were harvested by centrifugation at 4000g for 10 min and then immediately stored at –20 °C until analysis. The animals were sacrificed after bleeding, and tissues of brain, heart, lung, liver, spleen, kidney, and testis were collected. The tissues samples were homogenized in adequate volumes of isotonic saline (Tissue tearer, Biospec Co., Bartlesville, OK, USA) and stored at –20 °C until analysis. The partition coefficient (Kp) was calculated as the steady state tissue-to-plasma PE (or PAA) concentration ratio. The tissue and plasma PE and PAA concentrations determined at 2 h after intravenous infusion were used as the steady state concentrations.


Details on dosing and sampling:
I.v. experiment: Venous blood samples (approximately 0.2 mL) were collected from the jugular vein at 0, 2, 5, 10, 15, 30, 45 min, and 1, 1.5, 2, 2.5, 3, and 4 h after injection. Plasma samples were harvested by centrifugation at 4000 g for 10 min and stored at -20 °C until analysis. Urine samples were collected for 24 h after intravenous injection.
Dermal experiment: Blood samples (0.2 mL each) were collected from jugular vein at 0, 5, 15, 30, 45 min, and 1, 1.5, 2, 3, 4, 6, 8, and 12 h after topical application. Plasma samples were harvested by centrifugation at 4000 g for 10 min and stored at –20 °C until analysis.
Statistics:
Was performed.
Details on absorption:
See below under "Any other information ..."
Details on distribution in tissues:
Tissue distribution study
Due to continuous dermal exposure of PE as a preservative from cosmetic products, the tissue distribution characteristics of PE and PAA were determined under steady-state conditions. After the initiation of infusion, steady-state plasma concentrations of PE and PAA were achieved within 45 min and 1.25 h, respectively. The observed steady-state plasma PE concentrations (mean 113.4 ± 10.6 ng/mL) were comparable to the target concentration of 100 ng/mL. Throughout the infusion period, plasma PAA levels were consistently higher (305.0 ± 35.9 ng/mL) than corresponding PE levels. The steady-state concentrations of PE and PAA in plasma and 7 different tissues (liver, kidney, lung, testis, brain, spleen, and heart) were determined and also their tissue-to-plasma partition coefficients (Kp). For PE, the highest Kp was observed for kidney (Kp = 3.9) followed by spleen, heart, brain, testis, liver, and lung, with the Kp values greater than unity for all tissues but lung and liver.
For PAA, the highest Kp was also found for kidney (Kp = 5.0) followed by liver, heart, testis, spleen, and brain, and the Kp values were greater than unity for kidney, liver, lung, and testis only.
Details on excretion:
See below under "Any other information ..."
Metabolites identified:
yes
Details on metabolites:
Phenoxyacetic acid is the main metabolite of 2-phenoxyethanol.

Intravenous injection study:

This study was conducted to characterize the disposition of PE and to determine the absolute topical bioavailability. The average plasma concentration–time profiles of PE and PAA in rats after intravenous injection of PE (doses 0.2, 0.5, and 2 mg/kg) were obtained. After intravenous injection, PE was extensively converted to PAA, with the average PAA-to-PE AUC ratio (AUCPAA/AUCPE) of 5.2, 4.5, and 5.0 for the intravenous doses of 0.2, 0.5 and 2 mg/kg, respectively. The disposition of PE was characterized by a relatively small volume of distribution (Vz, 1.6–2.0 L/kg), high systemic clearance (Cls, 123–132 mL/min/kg), and short terminal half- life (t1/2, 10–11 min). These values remained unaltered as a function of the injected dose range of 0.2–2 mg/kg, indicating a dose-linear kinetics.

Immediately after injection of PE, PAA was formed rapidly, with the time to peak concentration (Tmax) of 9–10 min. For PAA, the average terminal half-life (15–34 min) and Tmax (9 – 10 min) also remained unaltered as a function of the injected dose.

PE was not excreted unchanged in urine, but PAA was found to be extensively excreted in urine (64.7–75.7% of the equivalent dose of PE).

Topical application study:

The in vivo percutaneous absorption of PE was characterized in rats after topical application of emulsion and lotion (applied dose of PE = 2.34 mg/kg). Upon topical application, both PE and PAA were quantifiable in the first plasma samples (5 min) and reached Cmax at approximately 1 h. The assay sensitivity was high enough to characterize the initial absorption and terminal elimination processes.

Following topical application, PE was rapidly absorbed and, throughout the sampling period, plasma PAA levels were consistently higher than corresponding PE levels.

The absolute topical bioavailability (F) of PE was high (mean 75.4% and 76.0% for emulsion and lotion, respectively). The apparent terminal half-life of PE found after topical application of emulsion and lotion (mean range, 96–102 min) was significantly longer than that found after intravenous injections (mean range, 10–11 min). Similarly, the apparent terminal half-life of PAA after topical application were significantly longer (108–126 min) than that found after intravenous injections (mean range 15–34 min). These observations indicate that the percutaneous absorption of PE and subsequent formation of PAA are slower than their respective elimination processes. The average AUCPAA/AUCPE ratios following topical application (mean range 4.4–5.3) were comparable to those found after intravenous injection (4.5–5.2). Although the skins are known to contain enzymes (alcohol dehydrogenase and aldehyde dehydrogenase), these comparable AUC ratios suggest that no significant dermal first-pass metabolism of PE occurred during the percutaneous penetration process.

Executive summary:

A LC-ESI–MS/MS method with polarity switching was developed and validated. It was applied for the simultaneous analysis of phenoxyethanol (PE) and its major metabolite, phenoxyacetic acid (PAA), in rat plasma, urine, and 7 different tissues. The percutaneous absorption, distribution, metabolism, and excretion were studied in rats.

The absolute topical bioavailability of PE was 75.4% and 76.0% for emulsion and lotion, respectively. Conversion of PE to PAA was extensive, with the average AUCPAA-to-AUCPEratio being 4.4 and 5.3 for emulsion and lotion, respectively.

Immediately after injection of PhE, PhAA was formed rapidly, with the time to peak concentration Tmax of 9–10 min. For PhAA, the average terminal half-life (15–34 min) and Tmax remained unaltered as a function of the injected dose. PhE was not excreted unchanged in urine, but PhAA was found to be extensively excreted in urine (64.7–75.7% of the equivalent dose of PhE).

The steady-state tissue-to-plasma PE concentration ratio (Kp) was higher than unity for kidney, spleen, heart, brain, and testis and was lower (≤0.6) for lung and liver, while the metabolite Kp ratio was higher than unity for kidney, liver, lung, and testis and was lower (≤0.3) for other tissues.

Description of key information

Phenoxy acetic acid and sodium phenoxyacetate are easily and practically completely absorbed after oral administration. The common anion phenoxyacetate is excreted practically completely and unchanged in urine (of rabbits).

 

Phenoxyethanol PhE, the metabolic precursor of sodium phenoxyacetate, is rapidly and rather completely absorbed after oral dosing (in rats, rabbits and human). PhE is rapidly metabolised predominantly to PhA- and rapidly excreted mainly as unchanged PhA-. More than 90 % of an oral dose of 2-phenoxyethanol was excreted in the urine of rats as phenoxyacetic acid within 24 h.

PhE is well absorbed through the skin, but not completely. Absorptions in the range of >59 to 78 % were reported. Remarkable is that after dermal exposure, PhE is metabolised to phenoxyacetate slower and to a lower extent (ca. 80 %) than after oral exposure, which is explained by an extensive first-pass metabolism in the liver for the oral route. The slower and lower metabolisation of topical applied PhE is used to explain the different toxic effects (haematotoxicity) observed by action of the unmetabolised PhE after dermal application (compared to the oral route), especially in the rabbit at higher doses.



Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
100

Additional information

Phenoxy acetic acid and sodium phenoxyacetate are easily and practically completely absorbed after oral administration. The common anion phenoxyacetate is excreted practically completely and unchanged in urine (of rabbits).

Accumulation: No accumulation is expected, based on the low log Pow and the good water solubility.